First-in-human (FIH) phase I study of the highly selective phosphoinositide 3-kinase inhibitor delta (PI3Kδ) inhibitor IOA-244 in patients with advanced cancer: Safety, activity, pharmacokinetic (PK), and pharmacodynamic (PD) results.
Authors: Anna Maria Di Giacomo, Federica Santangelo, Giovanni Amato, Elena Simonetti, Jill Graham, Michael M. F. Lahn, Lars Anders van der Veen, Zoe Johnson, Catherine Anne Pickering, Marco Durini, Ziyang Tan, Lakshmikanth Tadepally, Petter Brodin, Mariaelena Occhipinti, Matteo Simonelli, Carmelo Carlo-Stella, Armando Santoro, Pavlina Spiliopoulou, T.R. Jeffry Evans, Michele Maio
Journal: Journal of Clinical Oncology (2022)

3107 Background: T regulatory (Tregs) cells contribute to immune suppression in cancer. The highly selective inhibitor of PI3Kδ, IOA-244, blocks the activity of Tregs among other things, thus reprograms the anti-tumor immune response. Methods: IOA-244 was investigated in a two-part FIH study. Part A explored the continuous daily dosing of IOA-244 at 10, 20, 40 and 80 mg. Part B consists of expansion cohorts of specific tumor indications, including pre-treated uveal melanoma patients (pts). Primary objective: safety of the anticipated biologically effective dose (BED), or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1.-based responses; PFS and OS. Exploratory studies: changes in circulating immune cells by Cytometry by Time of Flight (CyTOF); response assessments by radiomics Results: Part A Solid Tumor (completed): Sixteen pts were treated in 4 cohorts each with 4 pts. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Four pts had at least one serious TEAE, none considered related to IOA-244. There was no treatment-emergent adverse events (TEAE) leading to study drug discontinuation, immune related toxicity or Dose Limiting Toxicity. CTCAE v5 Grade 1 and 2 were observed, including 2 cases of transient diarrhoea and 2 of AST/ALT elevation. Part A (Completed) – Subgroup Uveal Melanoma Pts (progressed ≥1 line prior therapy): 9 pts treated (3/9 pts ongoing). Mean time on treatment: 7.7 mo (range: 1.8-16.0 mo with 3 pts ongoing). ORR (RECIST 1.1): CR+PR: 0/9 (0%); SD: 6/9 (67%). Median OS: 5.4 mo - not determined (% alive at 1 year: 44% with 3 pts ongoing). CT images from 7/9 patients were assessed for changes in their metastatic lesions by radiomics (baseline and Week 8). Based on 147 matched lesions, 19% had complete responses and 16% had new lesions. In the liver, non-progressive disease was observed in 61% of all lesions, including 42% with either complete response or volume reduction of more than 30%. Using CyTOF, circulating Tregs were reduced while CD8 and NK cells were increased. Part B Uveal Melanoma Expansion Cohort (ongoing): 7 patients (7/7 pts ongoing); mean time on treatment 3.7 mo. ORR (RECIST 1.1): SD in 4/7 pts (57%). Part A Follicular Lymphoma Cohort (ongoing): At 20 mg: 4/4 pts. No DLT. At 80 mg: recruiting. Conclusions: In addition to being well tolerated, IOA-244 at the 80 mg dose shows reduction in peripheral blood Tregs and anti-tumor responses based on radiomics. Therefore, RECIST 1.1.-derived SD may underestimate anti-tumor activity of IOA-244 in treatment-resistant uveal melanoma. Additional patients will be treated to further refine this radiomics-based observation. Clinical trial information: NCT04328844.